This application focuses on one of the major causes of cardiovascular disease, namely myocardial ischemia. The general objectives of this proposal are to study the determinants and consequences of myocardial ischemia, including arrhythmogenesis, altered substrate metabolism, receptor and biochemical regulation at the cellular level, and neuro-humoral involvement. These studies will be conducted in dogs, pigs, rabbits, hamsters, and rats. They include: (1) studies of the determinants and regulation of total and transmural myocardial blood flow; (2) the functional, blood flow, and biochemical consequences for high energy phosphates and carbohydrate metabolism of ventricular hypertrophy due to aortic stenosis; (3) the effects of hypoxia and ischemia on adrenergic and histaminergic receptors, transmembrane signalling and cytoskeletal changes, as well as arrhythmogenesis; (4) the effects of ischemia and atrial natriopeptide on chemosensitive nerve endings in the heart, afferent nerve traffic, and reflex control of the coronary circulation; (5) the effects of ischemia and infarction on myocardial sympathetic innervation and arrhythmogenesis; and (6) the development of contrast enhancing agents for magnetic resonance imaging of myocardial perfusion and blood volume, and the use of these agents to evaluate subendocardial ischemia and myocardial infarcts.